US9121858B2 - Methods and kits for detecting cardiac remodeling in subjects without clinical signs of heart failure - Google Patents
Methods and kits for detecting cardiac remodeling in subjects without clinical signs of heart failure Download PDFInfo
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- US9121858B2 US9121858B2 US14/351,579 US201214351579A US9121858B2 US 9121858 B2 US9121858 B2 US 9121858B2 US 201214351579 A US201214351579 A US 201214351579A US 9121858 B2 US9121858 B2 US 9121858B2
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- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5091—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing the pathological state of an organism
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
- C12Q1/37—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase involving peptidase or proteinase
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/90—Enzymes; Proenzymes
- G01N2333/914—Hydrolases (3)
- G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
- G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
- G01N2333/964—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue
- G01N2333/96425—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals
- G01N2333/96427—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general
- G01N2333/9643—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general with EC number
- G01N2333/96486—Metalloendopeptidases (3.4.24)
- G01N2333/96491—Metalloendopeptidases (3.4.24) with definite EC number
- G01N2333/96494—Matrix metalloproteases, e. g. 3.4.24.7
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/32—Cardiovascular disorders
Definitions
- the present invention relates to methods and kits for detecting cardiac remodeling in subjects without clinical signs of heart failure.
- Heart failure is a major and growing public health problem in the United States. Approximately 5 million patients in this country have HF, and over 550,000 patients are diagnosed with HF for the first time each year. Heart failure is the primary reason for 12 to 15 million office visits and 6.5 million hospital days each year.
- Heart failure is a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.
- the cardinal manifestations of HF are dyspnea and fatigue (which may limit exercise tolerance) and fluid retention (which may lead to pulmonary congestion and peripheral edema). Both abnormalities can impair the functional capacity and quality of life of affected subjects.
- Heart failure may result from disorders of the pericardium, myocardium, endocardium or great vessels, but the majority of patients with HF have symptoms due to an impairment of left ventricular (LV) myocardial function.
- LV myocardial dysfunction begins with some injury to, or stress on, the myocardium and is generally a progressive process, even in the absence of a new identifiable insult to the heart.
- the principal manifestation of such progression is a change in the geometry and structure of the LV, such that the chamber dilates and/or hypertrophies and becomes more spherical, a process referred to as cardiac remodeling.
- This change in chamber size and structure not only increases the hemodynamic stresses on the walls of the failing heart and depresses its mechanical performance but may also increase regurgitant flow through the mitral valve. These effects, in turn, serve to sustain and exacerbate the remodeling process.
- Cardiac remodeling generally precedes the development of symptoms (sometimes by months or even years), continues after the appearance of symptoms, and contributes substantially to worsening of symptoms
- kits for detecting early cardiac remodeling in subjects without clinical signs of heart failure are highly desirable, especially in subjects at risk such as obese subjects.
- the present invention relates to a method for detecting cardiac remodeling in a subject without clinical signs of heart failure comprising determining the level of the NGAL-MMP9 complex in a blood sample obtained from the patient.
- NGAL-MMP-9 was found significantly associated with both plasma Aldo levels, and cardiac fibrosis biomarkers. This suggests that NGAL-MMP-9 was already altered at the early stage of cardiac remodeling that precedes clinical HF, and may therefore be a key-factor in the Aldo signaling pathway leading to tissue remodeling and heart failure.
- the present invention relates to a method for detecting cardiac remodeling in a subject without clinical signs of heart failure comprising determining the level of the NGAL-MMP9 complex in a blood sample obtained from the patient.
- cardiac remodeling refers to a compensatory physiologic response to an event or condition that compromises cardiac function. Triggers for cardiac remodeling include myocardial infarction, hypertension, wall stress, inflammation, pressure overload, and volume overload. Alterations in myocardial structure can occur as quickly as within a few hours of injury, and may progress over months and years.
- cardiac remodeling encompasses the global, cellular, and genetic changes that lead to alterations in the ventricular shape and function. While initially beneficial, these changes over time (months to years) can impair myocardial function to the point of chronic intractable heart failure.
- cardiac remodeling The hallmarks of cardiac remodeling are manifested as chamber dilation, increase in ventricular sphericity, and the development of interstitial and perivascular fibrosis. Increased sphericity is positively associated with mitral regurgitation. Ventricular dilation mainly results from cardiomyocyte hypertrophy and lengthening, and to a lesser extent from increases in the ventricular mass.
- the method of the invention is particularly suitable for detecting cardiac remodeling mediated by aldosterone.
- heart failure refers to any condition that can result from any structural or functional cardiac disorder that impairs the ability of the heart (e.g., the ventricle) to fill with or eject blood.
- a subject without clinical signs of heart failure is a subject classified at stage A of heart failure.
- the development of HF can be indeed characterized by considering 4 stages of the disease.
- the first stage, Stage A is a subject at high risk for HF but without structural heart disease, clinical signs or symptoms of HF (for example, these are patients with hypertension, atherosclerotic disease, diabetes, obesity, metabolic syndrome or patients using cardiotoxins).
- the second stage, Stage B is a subject having structural heart disease but without signs or symptoms of HF (for example, these are patients who have previously had obesity, exhibit LV remodeling including LV hypertrophy).
- the third stage, Stage C is a subject having structural heart disease with prior or current symptoms of HF (for example, these are patients who have known structural heart disease and exhibit shortness of breath and fatigue and have reduced exercise tolerance).
- the fourth and final stage, Stage D is refractory HF requiring specialized interventions (for example, patients who have marked symptoms at rest despite maximal medical therapy (namely, those who are recurrently hospitalized or cannot be safely discharged from the hospital without specialized interventions).
- the subject is an obese subject, and preferably a subject with abdominal obesity (>94 cm for male and >80 cm for female).
- blood sample is meant a volume of whole blood or fraction thereof, eg, serum, plasma, etc.
- NGAL neutrophil gelatinase
- MMP-9 matrix metalloproteinase 9, “MMP-9”
- NGAL-MMP9 complex intermolecular disulphide bridge as a 135-kDa heterodimeric form
- the methods of the invention comprise contacting the blood sample with a binding partner capable of selectively interacting with the biomarker protein present in the blood sample.
- the binding partner may be an antibody that may be polyclonal or monoclonal, preferably monoclonal. In another embodiment, the binding partner may be an aptamer.
- the binding partner is specific for the NGAL-MMP9 complex, namely has a higher affinity for the NGAL-MMP9 complex than for NGAL or MMP9 alone.
- the cross reaction between the NGAL-MMP9 and NGAL or MMP9 is low even null.
- the affinity of the binding partner is at least 10, preferably 100, more preferably 1000 or even more preferably 10000 higher that the affinity for NGAL or MMP9 alone.
- Epitope binning can be used to identify binding partners that fall within the scope of the claimed invention.
- Epitope binning refers to the use of competitive binding assays to identity binding partners that are, or are not capable of binding NGAL-MMP9 complex simultaneously with NGAL or MMP9, thereby identifying binding partners that bind to epitopes on NGAL-MMP9 that are not retrived in NGAL or MMP9.
- Epitope binning experiments provide evidence that antigenically distinct epitopes are present.
- the binding partners and typically antibodies of the present invention may be assayed for specific binding by any method known in the art.
- the immunoassays which can be used include, but are not limited to, competitive assay systems using techniques such western blots, radioimmunoassays, ELISA, “sandwich” immunoassays, immunoprecipitation assays, precipitin assays, gel diffusion precipitin assays, immunoradiometric assays, fluorescent immunoassays, protein A immunoassays, and complement-fixation assays.
- Such assays are routine and well known in the art (see, e.g., Ausubel et al., eds, 1994 Current Protocols in Molecular Biology, Vol.
- BIACORE® GE Healthcare, Piscataway, N.J.
- surface plasmon resonance assay formats that are routinely used to epitope bin panels of monoclonal antibodies.
- routine cross-blocking assays such as those described in Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory, Ed Harlow and David Lane, 1988, can be performed.
- Polyclonal antibodies of the invention or a fragment thereof can be raised according to known methods by administering the appropriate antigen or epitope to a host animal selected, e.g., from pigs, cows, horses, rabbits, goats, sheep, and mice, among others.
- a host animal selected, e.g., from pigs, cows, horses, rabbits, goats, sheep, and mice, among others.
- Various adjuvants known in the art can be used to enhance antibody production.
- antibodies useful in practicing the invention can be polyclonal, monoclonal antibodies are preferred.
- Monoclonal antibodies of the invention or a fragment thereof can be prepared and isolated using any technique that provides for the production of antibody molecules by continuous cell lines in culture.
- Techniques for production and isolation include but are not limited to the hybridoma technique originally described by Kohler and Milstein (1975); the human B-cell hybridoma technique (Cote et al., 1983); and the EBV-hybridoma technique (Cole et al. 1985).
- Antibodies useful in practicing the present invention also include anti-NGAL-MMP9 complex fragments including but not limited to F(ab′)2 fragments, which can be generated by pepsin digestion of an intact antibody molecule, and Fab fragments, which can be generated by reducing the disulfide bridges of the F(ab′)2 fragments.
- Fab and/or scFv expression libraries can be constructed to allow rapid identification of fragments having the desired specificity to NGAL-MMP9 complex. For example, phage display of antibodies may be used.
- single-chain Fv (scFv) or Fab fragments are expressed on the surface of a suitable bacteriophage, e. g., M13.
- a suitable host e. g., mouse
- the coding regions of the VL and VH chains are obtained from those cells that are producing the desired antibody against the protein. These coding regions are then fused to a terminus of a phage sequence.
- a suitable carrier e. g., bacteria
- the phage displays the antibody fragment.
- Phage display of antibodies may also be provided by combinatorial methods known to those skilled in the art. Antibody fragments displayed by a phage may then be used as part of an immunoassay.
- the binding partner may be an aptamer.
- Aptamers are a class of molecule that represents an alternative to antibodies in term of molecular recognition. Aptamers are oligonucleotide or oligopeptide sequences with the capacity to recognize virtually any class of target molecules with high affinity and specificity.
- ligands may be isolated through Systematic Evolution of Ligands by EXponential enrichment (SELEX) of a random sequence library, as described in Tuerk C. 1997.
- the random sequence library is obtainable by combinatorial chemical synthesis of DNA. In this library, each member is a linear oligomer, eventually chemically modified, of a unique sequence. Possible modifications, uses and advantages of this class of molecules have been reviewed in Jayasena S.
- Peptide aptamers consist of conformationally constrained antibody variable regions displayed by a platform protein, such as E. coli Thioredoxin A, that are selected from combinatorial libraries by two hybrid methods (Colas et al., 1996).
- binding partners of the invention such as antibodies or aptamers, may be labelled with a detectable molecule or substance, such as a fluorescent molecule, a radioactive molecule or any others labels known in the art.
- a detectable molecule or substance such as a fluorescent molecule, a radioactive molecule or any others labels known in the art.
- Labels are known in the art that generally provide (either directly or indirectly) a signal.
- the term “labelled”, with regard to the antibody is intended to encompass direct labelling of the antibody or aptamer by coupling (i.e., physically linking) a detectable substance, such as a radioactive agent or a fluorophore (e.g. fluorescein isothiocyanate (FITC) or phycoerythrin (PE) or Indocyanine (Cy5)) to the antibody or aptamer, as well as indirect labelling of the probe or antibody by reactivity with a detectable substance.
- a detectable substance such as a radioactive agent or a fluorophore (e.g. fluorescein isothiocyanate (FITC) or phycoerythrin (PE) or Indocyanine (Cy5)
- FITC fluorescein isothiocyanate
- PE phycoerythrin
- Indocyanine Indocyanine
- An antibody or aptamer of the invention may be labelled with a radioactive molecule by any method known in the art.
- the afore mentioned assays generally involve the binding of the binding partner (ie. antibody or aptamer) to a solid support.
- Solid supports which can be used in the practice of the invention include substrates such as nitrocellulose (e. g., in membrane or microtiter well form); polyvinylchloride (e. g., sheets or microtiter wells); polystyrene latex (e.g., beads or microtiter plates); polyvinylidine fluoride; diazotized paper; nylon membranes; activated beads, magnetically responsive beads, and the like.
- the level of biomarker protein may be measured by using standard immunodiagnostic techniques, including immunoassays such as competition, direct reaction, or sandwich type assays.
- immunoassays such as competition, direct reaction, or sandwich type assays.
- assays include, but are not limited to, agglutination tests; enzyme-labelled and mediated immunoassays, such as ELISAs; biotin/avidin type assays; radioimmunoassays; immunoelectrophoresis; immunoprecipitation.
- an ELISA method can be used, wherein the wells of a microtiter plate are coated with a set of antibodies which recognize said biomarker protein.
- a blood sample containing or suspected of containing said biomarker protein is then added to the coated wells.
- the plate(s) can be washed to remove unbound moieties and a detectably labelled secondary binding molecule added.
- the secondary binding molecule is allowed to react with any captured sample marker protein, the plate washed and the presence of the secondary binding molecule detected using methods well known in the art.
- Measuring the level of the biomarker protein may also include separation of the compounds: centrifugation based on the compound's molecular weight; electrophoresis based on mass and charge; HPLC based on hydrophobicity; size exclusion chromatography based on size; and solid-phase affinity based on the compound's affinity for the particular solid-phase that is used.
- said biomarker protein may be identified based on the known “separation profile” e. g., retention time, for that compound and measured using standard techniques.
- the separated compounds may be detected and measured by, for example, a mass spectrometer.
- the method of the invention further comprises a step consisting of comparing the determined level of NGAL-MMP9 complex in the blood sample obtained from the subject with a reference level, wherein a difference between said determined level and said reference level is indicative that cardiac remodeling, especially of cardiac remodeling mediated (but not exclusive to) by aldosterone, is present in said subject.
- the reference values may be index values or may be derived from one or more risk prediction algorithms or computed indices for cardiac remodeling.
- a reference value can be relative to a number or value derived from population studies, including without limitation, such subjects having similar body mass index, similar abdominal obesity, total cholesterol levels, LDL/HDL levels, systolic or diastolic blood pressure, subjects of the same or similar age range, subjects in the same or similar ethnic group . . . .
- the reference value is derived from the level of NGAL-MMP9 complex in a control sample derived from one or more subjects who are substantially healthy (i.e. having no cardiac remodeling or obesity).
- such subjects are monitored and/or periodically retested for a diagnostically relevant period of time (“longitudinal studies”) following such test to verify continued absence of cardiac remodeling.
- Such period of time may be one year, two years, two to five years, five years, five to ten years, ten years, or ten or more years from the initial testing date for determination of the reference value.
- retrospective measurement of NGAL-MMP9 complex levels in properly banked historical subject samples may be used in establishing these reference values, thus shortening the study time required, presuming the subjects have been appropriately followed during the intervening period through the intended horizon of the product claim.
- the levels of NGAL-MMP9 complex in a subject has cardiac remodeling is deemed to be higher than the reference value obtained from healthy subjects who have developed cardiac remodeling.
- the method of the invention is particularly suitable for the management and the appreciation of risk for heart failure. Accordingly, the present invention relates to a method for determining whether a subject is at risk of developing heart failure comprising a step consisting of detecting cardiac remodeling according to the method as above described.
- the subject when cardiac remodeling is detected by the method of the invention, then the subject may be administered with a mineralocorticoid antagonist.
- Mineral antagonists are well known in the art and include but are not limited to spirolactone-type steroidal compounds (such as spironolactone or eplerenone) or non steroidal compounds (Meyers, Marvin J1; Hu, Xiao Expert Opinion on Therapeutic Patents, Volume 17, Number 1, January 2007, pp. 17-23(7)).
- kits for performing a method of the invention comprising means for measuring the level of NGAL-MMP9 complex in a blood sample obtained from the subject.
- the kit may include an antibody, or a set of antibodies as above described.
- the antibody or set of antibodies are labelled as above described.
- the kit may also contain other suitably packaged reagents and materials needed for the particular detection protocol, including solid-phase matrices, if applicable, and standards.
- the kit may also contain one or more means for the detection of a further biomarker.
- the kit may also contain means for the detection of one ore more heart failure biomarker selected from the group consisting of brain natriuretic peptide (BNP), amino-terminal pro-brain natriuretic peptide (NT-pro BNP), norepinephrine, troponin, heart-type fatty acid binding protein, myosin light chain-1, matrix metalloproteinase, tissue inhibitor of matrix metalloproteinase, C-reactive protein (CRP), TNFalpha, soluble tumor necrosis factor receptor 1 (sTNFR1), soluble T2 receptor, soluble IL-2 receptor, CD40-CD154, CCAM-I, P-selectin, tissue factor and von Willebrand factor, urocortin, myeloperoxidase, and uric acid.
- BNP brain natriuretic peptide
- NT-pro BNP amino-terminal pro-brain natriuretic peptide
- norepinephrine trop
- FIG. 1 Correlation plots between NGAL-MMP-9 and aldosterone or collagen peptides in controls and obese subjects, and in the whole population. Correlation coefficients and 95% confidence intervals from non-parametric Spearman's analysis are indicated. Straight lines are the usual unadjusted regression lines (parametric analysis; continuous: all subjects, small dots: controls, large dots: abdominal obesity).
- Asymptomatic subjects 40-65 years) with abdominal obesity (AO) (>94 cm for male, >80 cm for female (Holt R I. International diabetes federation re-defines the metabolic syndrome. Diabetes Obes Metab. 2005; 7:618-620) and age-gender matched healthy volunteers (BMI ⁇ 25 kg/m 2 ) without AO were recruited through press advertisement.
- Known diabetic subjects, or participants with known or suspected hypertension at the screening visit ie blood pressure>140/90 mm Hg
- morbid obesity body mass index>40 kg/m 2
- personal history of cardiovascular events or of endocrine disease, inflammatory or neoplasic diseases were excluded.
- Written informed consent was obtained. The study was approved by the local ethics committee (CPP Est-III) and all subjects provided written informed consent.
- Cardiovascular and biological phenotyping included blood pressure measurements and Magnetic Resonance Imaging (MRI) to determine left ventricular mass (see infra).
- MRI Magnetic Resonance Imaging
- free NGAL D9L20, R&D Systems
- NGAL-MMP-9 complexes NGAL20, R&D Systems
- total NGAL was computed as the sum of free and NGAL-MMP-9.
- Radioimmunoassay kits (Orion Diagnostica, Espoo, Finland) were used for determinations of serum collagen peptides (PINP: aminoterminal propeptide of type I procollagen, aminoterminal propeptide of PIIINP procollagen type III, ICTP: type 1 collagen telopeptide) as reported (Iraqi W, Rossignol P, Angioi M, Fay R, Nuee J, Ketelslegers J M, Vincent J, Pitt B, Zannad F.
- PINP aminoterminal propeptide of type I procollagen
- ICTP type 1 collagen telopeptide
- Extracellular cardiac matrix biomarkers in patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure Insights from the eplerenone post-acute myocardial infarction heart failure efficacy and survival study (ephesus) study. Circulation. 2009; 119:2471-2479). The same operator performed these tests, blinded for subjects group.
- MRI was performed on a 1.5-T magnet (Signa Excite, GE Medical Systems, Milwaukee, Wis., USA) equipped with an 8-element phased-array surface coil.
- Main acquisition parameters were as follows: 8 mm slice-thickness, 3.5-3.9 ms repetition time, 14 to 16 K-space lines per segment, 30 phases per cardiac cycle with view sharing, field-of-view (FOV) ranging from 32 to 38 cm with a phase FOV of 0.9, and a 224 ⁇ 224 matrix.
- the left ventricular mass was determined on the contiguous SSFP short-axis slices, using dedicated software (MASSTM, Medis, The Netherlands).
- the left ventricular mass was determined at end-diastole, and papillary muscles and trabeculations were excluded for left ventricular mass measurement (Codreanu A, Djaballah W, Angioi M, et al. Detection of myocarditis by contrast-enhanced MRI in patients presenting with acute coronary syndrome but no coronary stenosis. J Magn Reson Imaging 2007; 25(5):957-964.; Mandry D, Lapicque F, Odille F, et al. Multicompartmental analysis of late contrast enhancement in areas of myocardial infarction supplied by chronically occluded coronary arteries. J Magn Reson Imaging 2009; 29(1):78-85.).
- AO displayed a 3.7 fold increase in NGAL-MMP-9 (p ⁇ 0.0001), a 70% increase in plasma Aldo levels (p ⁇ 0.0001), a 2.1 fold increase in PINP (p ⁇ 0.0001), and a 23% decrease in ICTP (p ⁇ 0.0001) (Table 1).
- No significant correlation was observed between free NGAL or total NGAL and plasma Aldo, or with extracellular matrix biomarkers.
- NGAL-MMP-9 was positively significantly correlated with plasma Aldo, PINP, PIIINP and negatively correlated with ICTP, a correlation mainly driven by the AO group ( FIG. 1 ).
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Abstract
Description
TABLE 1 |
Study population features |
Controls | Abdominal obesity | |||
Median (IQR) | Median (IQR) | p value | ||
Age (years) | 54 | (50-58) | 55 | (51-59) | 0.45 |
Gender male: n (%) | 24 | (45) | 39 | (46) | 0.95 |
Weight (kg) | 61 | (57-71) | 89 | (77-96) | <0.0001 |
Height (cm) | 1.69 | (1.61-1.74) | 1.67 | (1.58-1.72) | 0.20 |
BMI (kg/m2) | 22.5 | (21.1-24.0) | 31.4 | (29.6-33.4) | <0.0001 |
Waist circumference | 78 | (70-85) | 102 | (96-108) | <0.0001 |
(cm) | |||||
SBP (mmHg) | 115 | (110-123) | 121 | (114-130) | 0.006 |
DBP (mmHg) | 72 | (66-76) | 73 | (68-79) | 0.25 |
MBP (mmHg) | 87 | (82-91) | 89 | (83-95) | 0.033 |
Heart rate (bpm) | 60 | (57-66) | 70 | (62-77) | <0.0001 |
Total cholesterol | 5.52 | (4.92-5.75) | 5.91 | (5.26-6.47) | 0.019 |
(mmol/l) | |||||
LDL-cholesterol | 3.37 | (3.03-3.99) | 3.63 | (3.19-4.10) | 0.14 |
(mmol/l) | |||||
HDL-cholesterol | 1.63 | (1.35-1.86) | 1.29 | (1.14-1.66) | 0.006 |
(mmol/l) | |||||
Triglycerides | 0.75 | (0.66-1.01) | 1.34 | (0.93-1.92) | <0.0001 |
(mmol/l) | |||||
Blood glucose | 4.83 | (4.44-5.16) | 5.00 | (4.72-5.33) | 0.046 |
(mmol/l) | |||||
C-reactive protein | 0.85 | (0.49-1.41) | 2.20 | (1.14-4.70) | <0.0001 |
(mg/l) | |||||
Estimated GFR | 76 | (67-83) | 78 | (68-84) | 0.87 |
(ml/min/1.73 m2) | |||||
NGAL (ng/ml) | 79.1 | (57.0-97.8) | 71.7 | (61.2-84.7) | 0.57 |
NGAL-MMP-9 | 1.20 | (0.10-2.80) | 4.40 | (1.90-11.60) | <0.0001 |
(ng/ml) | |||||
Total NGAL | 82.2 | (58.2-100.2) | 78.2 | (70.8-94.6) | 0.75 |
(ng/ml) | |||||
Aldosterone (pg/ml) | 39.4 | (27.1-46.6) | 55.3 | (38.2-84.3) | <0.0001 |
PINP (ng/ml) | 16.0 | (10.4-33.9) | 33.9 | (23.2-43.8) | <0.0001 |
PIIINP (ng/ml) | 2.10 | (0.10-3.20) | 2.70 | (2.00-3.30) | 0.20 |
ICTP (ng/ml) | 4.50 | (4.00-5.10) | 3.50 | (3.05-4.25) | <0.0001 |
Left ventricular | |||||
mass | |||||
g | 78 | (71-98) | 90 | (75-110) | 0.047 |
g/m2 BSA | 47 | (43-52) | 43 | (38-52) | 0.061 |
p-value from the non parametric Mann-Whitney test for continuous variables, from the Chi-Square test for gender. | |||||
BMI, body mass index; | |||||
SBP, systolic blood pressure; | |||||
DBP, diastolic blood pressure; | |||||
MBP, mean blood pressure; | |||||
GFR, glomerular filtration rate. |
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US4946778A (en) | 1987-09-21 | 1990-08-07 | Genex Corporation | Single polypeptide chain binding molecules |
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2012
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- 2012-10-12 WO PCT/EP2012/070268 patent/WO2013053894A1/en active Application Filing
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Patent Citations (2)
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US20140248284A1 (en) * | 2011-10-20 | 2014-09-04 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Methods for the detection and the treatment of cardiac remodeling |
US20150005260A1 (en) * | 2012-01-02 | 2015-01-01 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Methods for the detection and the treatment of diastolic dysfunction |
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EP2766732A1 (en) | 2014-08-20 |
EP2766732B1 (en) | 2015-09-16 |
US20140249121A1 (en) | 2014-09-04 |
WO2013053894A1 (en) | 2013-04-18 |
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